核因子-κB抑制剂对孕期感染鼠子代神经发育缺陷的干预研究

Effect of pyrrolidinedithiocarbamate on neural developmental disorder of adult offspring with maternal systemic exposure to Poly （I： C ） during pregnancy

目的探讨孕期感染鼠母体细胞因子介导的免疫激活与子代神经发育缺陷之间的关系以及核因子－KB抑制剂的干预效果。方法 60只大鼠随机分为三组，40只大鼠在孕早期应用Poly（I：C）制造孕鼠感染模型，每20只分别为模型组和干预组，干预组应用NF—KB抑制剂吡咯烷二硫基甲酸盐（PDTC）阻断相关的细胞因子表达，20只大鼠给予安慰剂注射作为对照。每组半数处死ELISA法检测母体血清1L-10和TNF—α水平，其余完成妊娠，对不同处理组孕鼠后代在成年期比较前脉冲抑制、被动回避和主动规避的不同。结果应用Poly（I：C）后，母体血清IL—10[对照组（0．16±O．13）pg／ml比模型组（18．26±1．52）pg／m1]和TNF-α对照组[（11．21±1．81）pg／ml比模型组（119．64±16．42）pg／m1]水平升高，同时子代成年期出现精神病样表现如前脉冲抑制、被动回避和主动规避的异常，PDTC呵可降低母体血清IL—10[干预组（12．64±2．04）pg／ml比模型组（18．26±1．52）pg／m1]和TNF—α：预组（30．34±2．19）pg／ml比模型组（119．64±16．42）pg／m1]水平，部分改善子代成年期出现的精神病样行为。结论 PDTC通过降低孕鼠感染后细胞因子介导的母体炎性反应，可干预子代成年后的神经发育障碍。

Objective To explore the correlation between the elevated expression of cytokines under the induction of Poly （ I： C） （ polycytidylic acid） in maternal hosts and the abnormal behaviors of adult offsprings and understand the intervening effects of nuclear factor NF-KB inhibitor pyrrolidinedithiocarbamate （PDTC）. Methods Poly （I：C） or saline was administered to model the maternal infection during early pregnancy in rats. And the expression of eytokines was blocked with PDTC. The maternal levels of tumor necrosis factor alpha and interleukin-lO were determined by ELISA （enzyme-linked immunosorbent assay）. The adult offsprings on different treatments were then compared with regards to prepulse inhibition （ PPI）, passive avoidance and active avoidance. Results After the administration of Poly （ I ： C ） , there was an elevated levels of serum cytokines as shown by the markedly increased serum levels of IL-10 and TNF-α. The serum levels of IL-10 and TNF-α in the model group were significantly higher than those in the control group [（18.26±1.52） pg/ml, （119.64±16.42） pg/mlvs. （0.16±0.13） pg/mland （11.21 ±1.81） pg/ml ]. The elevation was partly blocked by PDTC. The serum levels of IL-10 and TNF-a in the intervention group [ （12. 64 ±2. 04） pg,/ml and （30. 34 ±2. 19） pg/ml respectively] were lower than those in the model group, but still higher than those in the control group. The psychotic-like phenotypes including defects in PPI, passive avoidance and active avoidance were observed in Poly（ I： C）-treated offsprings. Such an effect was blunted by the PDTC intervention. The PPI results demonstrated that the PP2 and PPs difference between rats in 3 groups were statistically significant, with a lower PPI value in the model group than in theintervention group, in the intervention group than in the control group and much lower in the model group than in the control group. PP4 was lower in the model group than that in the intervenlion group, and also lower in the model group than in the control group. There was no significant difference between the control group and the intervention group. The passive avoidance results indicated that T1 was higher in the model group than in the control and intervention groups and there was no statistical difference between the control and intervention groups. T2 was lower in the model group than in the control and intervention groups and there was no statistical difference between the control and intervention groups. And the active avoidance test results showed that total conditioned reflex times of the control group was higher than those of the intervention and model groups. No statistical difference was found between the intervention and model groups. Total reflex rate of the control group was higher than that of the intervention and model groups. No statistical difference was found between the intervention and model groups. Conclusion PDTC can interfere with neural developmental disorder of adult offsprings through blunting the cytokine-mediated maternal immune response.